Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Thomas W. Winkler*, Humaira Rasheed, Lifelines Cohort Study, DiscovEHR/MyCode study, VA Million Veteran Program, Alexander Teumer, Mathias Gorski, Bryce X. Rowan, Kira J. Stanzick, Laurent F. Thomas, Adrienne Tin, Anselm Hoppmann, Audrey Y. Chu, Bamidele Tayo, Chris H.L. Thio, Daniele Cusi, Jin Fang Chai, Karsten B. Sieber, Katrin Horn, Man LiMarkus Scholz, Massimiliano Cocca, Matthias Wuttke, Peter J. van der Most, Qiong Yang, Sahar Ghasemi, Teresa Nutile, Yong Li, Giulia Pontali, Felix Günther, Abbas Dehghan, Adolfo Correa, Afshin Parsa, Agnese Feresin, Aiko P.J. de Vries, Alan B. Zonderman, Albert V. Smith, Albertine J. Oldehinkel, Alessandro De Grandi, Alexander R. Rosenkranz, Fernando Rivadeneira, Helena Schmidt, Janine F. Felix, M. Arfan Ikram, Maryam Kavousi, Mohsen Ghanbari, Niek Verweij, Raymond Noordam, Sanaz Sedaghat, Suzanne Vogelezang, Tien Yin Wong, Vincent W.V. Jaddoe, Ya Xing Wang

*Corresponding author for this work

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Abstract

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

Original languageEnglish
Article number580
JournalCommunications Biology
Volume5
Issue number1
DOIs
Publication statusPublished - 13 Jun 2022

Bibliographical note

Funding
Open Access funding enabled and organized by Projekt DEAL.

Publisher Copyright: © 2022, The Author(s).

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